It has been known for decades that more than a dozen unrelated proteins can undergo aberrant assembly in vivo to form filaments or fibrils, which are generally referred to as amyloid (for reviews, see Sacchettini and Kelly, Nature Rev. 1:267-75, 2002; Stefani and Dobson, J. Mol. Med. 81:678-99, 2003; Lansbury and Lashuel, Nature 443:774-79, 2006). The presence of extracellular or intracellular aggregates of a specific polypeptide molecule is a hallmark of the recognized amyloid diseases; such aggregates promoting aggregation-mediated proteotoxicity. The polypeptides involved include full-length proteins (e.g., lysozyme and immunoglobulin light chains), peptides (e.g., amylin and atrial natriuretic factor) and fragments of larger proteins produced as a result of normal or abnormal endoproteolytic processing (e.g., Alzheimer's β-amyloid peptide). Abnormal processing is often the result of misfolding (Golde et al., Science 255:728-30, 1992; Shoji et al., Science 258:126-29, 1992; Kimberly et al., J. Biol. Chem. 275:3173-78, 2000). Nearly all full-length amyloidogenic proteins are secreted, suggesting that these proteins misfold after export (Kelly, Structure 5:595-600, 1997; Moyer and Balch, Emerging Therap. Targets 5:165-76, 2001). In some cases the proteins involved have wild-type sequences, as in sporadic forms of the diseases, but in other cases these are variants resulting from genetic mutations associated with familial forms of the diseases.
The presence of misfolded or aggregated proteins triggers a complex biological response, leading to the expression, among others, of the genes for heat shock proteins (Hsp, or molecular chaperone proteins) and proteins involved in the ubiquitin-proteasome pathway (Sherman and Goldberg, Neuron 29: 15-32, 2001). The evolution of such complex biochemical machinery makes clear the fact that it is necessary for cells to isolate and rapidly and efficiently clear any unfolded or misfolded protein as soon as it appears. Until recently, the main amyloid diseases were thought to be restricted to Alzheimer's disease (AD), Parkinson's disease (PD), reactive amyloidosis and the systemic amyloidoses (e.g., immunoglobulin-light-chain-, transthyretin- and gelsolin-based diseases) (Westermark et al, Proc. Natl. Acad. Sci. USA 87:2843-45, 1990; Hurle et al., Proc. Natl. Acad. Sci. USA 91:5446-50, 1994; Selkoe, Science 275:630-31, 1997; Kiuru, Amyloid 5:55-66, 1998). However, amyloid-like disorders are likely far more widespread than previously thought, and could include many common neurodegenerative and neuromuscular pathologies, as well as prion disease. The most intensely studied amyloid disease is AD, where characteristic brain plaques contain β-amyloid. The primary biochemical component of β-amyloid is a 39- to 43-amino acid peptide derived from the β-amyloid precursor protein (APP) through endoproteolysis (Glenner and Wong, Biochem. Biophys. Res. Commun. 83:885-90, 1984).
The deposition of proteins in the form of amyloid fibrils and plaques is the characteristic feature of more than twenty degenerative conditions affecting either the central nervous system or a variety of peripheral tissues.